Abstract
Dandy-Walker malformation (DWM; OMIM #220200) is a common but poorly understood congenital cerebellar malformation in humans. Through physical mapping of 3q2 interstitial deletions in several individuals with DWM, we defined the first critical region associated with DWM, encompassing two adjacent Zinc finger in cerebellum genes, ZIC1 and ZIC4. Mice with a heterozygous deletion of these two linked genes have a phenotype that closely resembles DWM, providing a mouse model for this malformation.
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Acknowledgements
We thank the affected individuals and their families for their participation, P. Soriano for providing the pPGKneo DTA vector and E. McNally and C. Roe for discussions and reading the manuscript. This work was supported by a Ragins-Goldsmith Fellowship and the Medical Scientist Training grant (to I.G.), a grant from the Brain Research Foundation of Chicago (to K.J.M.) and grants from the National Institute of Health (to K.J.M. and W.B.D.).
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Supplementary information
Supplementary Fig. 1
Axial CT scan from patient LR01-325. (PDF 82 kb)
Supplementary Fig. 2
In situ analysis showing Zic1 and Zic4 expression in the developing CNS, including the developing cerebellum. (PDF 165 kb)
Supplementary Fig. 3
Altered expression of ZIC1 and ZIC4 in patient LR01-325. (PDF 78 kb)
Supplementary Fig. 4
Vermis as a percentage of hemisphere width for each genotype at P22. (PDF 51 kb)
Supplementary Table 1
Phenotype summary of patients with del 3q2. (PDF 2 kb)
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Grinberg, I., Northrup, H., Ardinger, H. et al. Heterozygous deletion of the linked genes ZIC1 and ZIC4 is involved in Dandy-Walker malformation. Nat Genet 36, 1053–1055 (2004). https://doi.org/10.1038/ng1420
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DOI: https://doi.org/10.1038/ng1420
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